Candida albicans (CA) colonization is required for invasive disease. Adult mice are resistant to CA gastrointestinal (GI) colonization. We have identified two genetically distinct anaerobic commensal bacteria that can individually maintain CA colonization resistance in germ-free mice. These anaerobic commensals induce host immune effectors (transcription factor, HIF1-?, and antimicrobial peptide, CRAMP/LL-37) that significantly decrease CA GI colonization. By pharmacologically inducing both HIF1-? and CRAMP, we were able to significantly reduce CA colonization and reduce mortality from CA dissemination by 50%. Interestingly, the anaerobic bacteria that can expel CA from the gut share the ability to produce short-chain fatty acids (SCFAs). SCFAS have been shown to have numerous immunomodulatory properties. Therefore, my central hypothesis is that SCFAs produced by gut commensal anaerobic bacteria are necessary to maintain CA colonization resistance. This work will involve two specific aims. First, I will determine whether SCFAs are necessary for CA colonization resistance. I will evaluate whether commensal anaerobe Bacteroides thetaiotamicron mutants unable to produce SCFAs or SCFAs alone can reduce CA colonization. I predict that SCFAs are necessary for maintaining CA colonization resistance. Second, I will determine if HIF-1? and/or CRAMP are necessary for SCFA-induced GI colonization reduction. I will evaluate whether SCFAs can promote CA clearance in cultured human and mouse gut epithelial cells and CA colonization reduction in Hif1a and Cramp knockout mice. I predict that HIF1-? and CRAMP are necessary for maintaining CA colonization resistance. Given the high morbidity and mortality associated with invasive fungal infections, the limited arsenal of antifungal antibiotics, and the continuing emergence of antibiotic resistant strains, new approaches to treating and preventing invasive fungal infections in patients are desperately needed. Using natural occurring anaerobic bacterial metabolites (SCFAs) to boost GI mucosal immune effectors to reduce fungal colonization and ultimately decrease dissemination could represent paradigm shift in the way we prevent/treat fungal infections in patients. These studies will lay the groundwork for the following innovations: 1) a novel mechanism by which SCFAs activate gut immune defenses to maintain CA colonization resistance; 2) a novel approach (SCFAs) to inhibit CA dissemination; and 3) a novel approach to preventing fungal infections in patients. Together, these studies should lead to fundamental insights into bacterial/fungal interactions within the intestinal tract and will provide new perspectives in combating invasive fungal disease in the human host.